UNRAVELLING THE PATHOGENETIC MECHANISMS OF ARX MUTATIONS LEADING TO SEVERAL FORMS OF MENTAL RETARDATION, EPILEPSY AND XLAG

Mental retardation (MR) and epilepsy are common, affecting 2-3% of the population. They often occur together and in a large proportion of cases (~50%) they are of genetic origin. Major advances in the elucidation of the monogenic causes of mental retardation and epilepsy has recently been achieved, in particular for forms of X-chromosome linked mental retardation (or XLMR) and idiopathic epilepsy. However, little is known for a group of heterogeneous epileptic syndromes leading in most of the cases to strong mental retardation affecting children and newborns, named generally infantile spasms (IS). In particular, the triad of IS, hypsarrhythmia in the electroencephalogram (EEG) and developmental arrest is called West syndrome (WS; OMIM#308350) and shows a heterogeneous aetiology which includes various genetic forms. Recently, mutations in the ARX gene have been shown to lead to a variety of MR and epilepsy forms, including syndromic and non-specific MR, myoclonic epilepsy associated to spasticity, West and Partington syndromes and autism-like behaviour. The lack of knowledge regarding the involved pathological mechanisms, prevents the understanding of why these patients regress and limited the therapeutic interventions aimed at improving cognitive outcome. We described the expression analysis of the murine ARX horthologue gene and linked its activity to the mechanisms of cerebral cortical growth and GABAergic neural differentiation. These findings individuate an experimental framework where concentrate our studies toward the identification of the molecular function played by Arx. In order to reach this goal, we have developed innovative animal models missing the Arx functional activity either generally or specifically in the GABAergic system. Molecular and genetic studies on these animals will largely improve our knowledge on the Arx functions and will be pivotal in designing novel therapeutic approaches.